The aim of this project is to understand how Fc receptors communicate intracellular signals to initiate mast cell activation leading to inflammation. We have focused on signaling proteins that may serve as possible links from Fc receptor to gene expression and mast cell degranulation and on how this receptors activity is regulated.[unreadable] [unreadable] Results: The objectives of the past year were met in the following manner. First, Studies on the role of two different isoforms of Lyn kinase that associate with the IgE receptor were initiated. These studies led us to explore the influence of genetics on the role of these kinases and their ability to activate mast cells. We found that differences in the genetic background of mice has a dramatic effect both on the function of these kinases and their control on mast cell responses. Second, additional work explored whether other stimuli that lead to mast cell activation functioned through the use of Lyn or Fyn. We found that oxidative stress preferentially activates cytokine gene expression through the use of Fyn kinase. Third, we also have initial findings suggesting that Fyn kinase interacts with the beta subunit of the IgE receptor and that it may compete with Lyn for this binding. This suggest the existence of receptor heterogeniety, some associated with Fyn whereas others with Lyn. Fourth: Addtionally, the work of this year also led to the discovery that their is differential dephosphorylation of the two tyrosine resdiues found in the cytoplasmic domain of the gamma subunit of the IgE receptor and that this is important as a inactivation step that controls the extent of mast cell activation by controlling the activation of Syk kinase, a kinase that amplifies IgE receptor signalling. Finally, our studies also show that the IgE receptor alpha chain, which binds IgE, is expressed in cells outside of the immune system. Specifically, we found that the alpha chain is epxressed in pinealocytes, the cells that regulate circadian cycle suggesting a possible link neuroendocrine-immune link. [unreadable] [unreadable] Conclusions and Significance: In summary, we found that both Fyn and Lyn kinases function is regulated in the context of other genes, as it was found that mice with differing genetic backgrounds had different kinase levels and mast cell responses were influenced by the levels of the kinases being expressed. We also found that stress can induce mast cell responses through activation of Fyn kinase and the p38MAPK. Finally, the existence of IgE receptors on cells with neuroendocrine function was unexpected but provides a possible link between the stress or circadian cycles which activates cells like pinealocytes and the immune response. These findings provide new avenues for future exploration toewards understanding the role of IgE Fc receptors in health and disease.